Drug delivery device with cartridge piercing when cap is pulled off

ABSTRACT

The disclosure relates to a drug delivery device for dispensing a liquid drug through a needle with a proximal and a distal needle tip, comprising
         a body,   a needle holder holding the needle relative to the body,   a cartridge holder holding a cartridge comprising the liquid drug sealed with a septum on a distal end and with a movable stopper on a proximal end, and   a cap adapted to cover at least the distal needle tip of the needle,   wherein the cartridge holder is movable relative to the body from a retracted position   towards an advanced position, thereby piercing the proximal needle tipthrough the septum, characterized in that the cap is releasably engaged with the cartridge holder, wherein the cap is released from the cartridge holder in its advanced position.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is the national stage entry of InternationalPatent Application No. PCT/EP2016/063698, filed on Jun. 15, 2016, andclaims priority to Application No. EP 15173167.6, filed in on Jun. 22,2015, the disclosures of which are expressly incorporated herein inentirety by reference thereto.

TECHNICAL FIELD

The disclosure relates to a drug delivery device for delivering a liquiddrug stored in a cartridge that is sealed with a septum, wherein thedrug delivery device comprises an injection needle that is covered by acap.

BACKGROUND

Pre-filled cartridges with a liquid drug are well known in connectionwith drug delivery devices to deliver the liquid drug by means of aninjection needle with a distal needle tip adapted to penetrate tissue.To prevent a negative impact on the liquid drug during storage, yet toease the preparation of an injection, it is known from the state of theart to seal pre-filled cartridges with a septum that is penetrated by aproximal needle tip of the injection needle immediately before theinjection. Also, caps for covering at least the distal needle tip of aninjection needle in order to prevent accidental needle sticks are knownfor such drug delivery devices. According to the state of the art, auser removes the cap and loads a pre-filled cartridge into the drugdelivery device such that the proximal needle tip of the injectionneedle pierces through the septum of the pre-filled cartridge in orderto prepare an injection.

SUMMARY

Certain aspects of the present disclosure can be implemented to providean improved drug delivery device for cartridges pre-filled with a liquiddrug that eases the preparation of an injection while retaining theprotection against accidental needle sticks as well as the protection ofthe liquid medicament from negative impacts during storage.

The aspects are implemented by a drug delivery device according to claim1.

Exemplary embodiments of the disclosure are given in the dependentclaims.

In the context of this specification, the terms distal and proximal aredefined from the point of view of a person performing an injection.Consequently, a distal direction refers to a direction pointing towardsthe site of an injection and a distal end defines an end of an elementthat is directed towards the site of the injection. Respectively, theproximal end of an element or the proximal direction is directed awayfrom the site of the injection and opposite to the distal end or distaldirection.

According to the disclosure, a drug delivery device for dispensing aliquid drug comprises

-   -   a body configured to house a cartridge comprising the liquid        drug sealed with a septum and with a movable stopper,    -   a needle holder holding a needle with a proximal and a distal        needle tip relative to the body, and    -   a cap adapted to cover at least the distal needle tip.

The cartridge is movable relative to the body from a retracted positiontowards an advanced position, wherein the proximal needle tip penetratesthe septum when the cartridge holder is moved from its retracted intoits advanced position. The cap is releasably engaged with the cartridge,wherein the cap is released from the cartridge in its advanced position.

While moving the cartridge towards the advanced position, the proximalneedle tip pierces the septum and extends through the septum and the capis being released from the cartridge. When the cartridge reaches itsadvanced position, the cap is released and, therefore, decoupled fromthe cartridge.

In order to prepare an injection, the cap is pulled off the drugdelivery device in a distal direction. Alternatively, the drug deliverydevice is triggered so that the cartridge is advanced within thehousing.

As the cap is engaged with the cartridge, the cartridge is moved fromits retracted into its advanced position by pulling off the cap in thedistal direction. Alternatively, after triggering of the drug deliverydevice, the cartridge is pushed forwards and takes along the cap.

Thereby, the proximal needle tip penetrates the septum such that theliquid drug can be expelled through the needle when the stopper of thecartridge is moved distally. Thus, the drug delivery device is preparedfor an injection by pulling off the cap or by triggering the drugdelivery device as a single user interaction. It is therefore notnecessary to unpack and assemble a needle in such a drug delivery devicewith a cartridge. Thus, the same convenience and efficiency is reachedas with prefilled syringes while advantageously retaining the liquiddrug sealed in the cartridge for improved and prolonged storage.

In an embodiment of the drug delivery device, a cartridge holder holdsthe cartridge, wherein the cartridge holder comprises a lever protrudingin a distal direction beyond the needle holder. On the distal end of thelever, a catch protrudes in an inwardly radial direction, i.e. directedtowards a central longitudinal axis. The catch is releasably engagedwith an angular recess formed in an inner surface of the needle cap,wherein the needle holder engages the lever such that the distal leverend is bended in an outwardly radial direction when the cartridge holderis moved towards the advanced position, thereby disengaging the radialcatch from the angular recess. The needle holder may be formed as asocket with a radially protruding flange such that the lever engages andis bended by the flange.

As the catch via the lever reliably transfers a pulling force in adistal direction onto the cartridge holder, the cartridge holder isreliably brought towards its advanced position, thereby reliablypenetrating the septum of the cartridge. As the catch disengages fromthe cap once the cartridge holder reached its advanced position, the capcan be removed from the drug delivery device particularly easy.

In another embodiment of a drug delivery device according to thedisclosure, the cap has an at least partially folded collar on its openproximal end. The folded collar engages a shoulder of a wall of thecartridge in its retracted position. The at least partially foldedcollar is guided in a guide recess formed between the cartridge wall andthe body when it is moved distally, thereby carrying the cartridgetowards its advanced position. A proximal protrusion of the needleholder proximally protrudes the circular flange when the cartridgereaches its advanced position, thereby causing the folded collar tounfold and disengage from the circular flange. As the folded collarunfolds, the cap may easily be removed off the cartridge holder and offthe drug delivery device.

In an embodiment, the folded collar may be formed by at least twocircumference arms that engage the flange of the cartridge wall. Thecircumference arms may be formed as bended or folded splines that areunbent or unfolded when the cap is pulled distally such thatcorresponding proximal protrusions of the needle holder meet thesefolded splines, thereby disengaging the flange of the cartridge wall.The circumference arms may be led through openings in the body. Holdingmembers of the body for holding the needle holder relative to the bodyare led through cut-outs in between the circumference arms.

In an embodiment of the drug delivery device, a stopper driver fordriving the stopper in a distal direction is integrated into thecartridge holder. The stopper driver may be formed as a pre-stressedspring that, upon unblocking, effects between a proximal end of thecartridge holder and the stopper. As an advantage, upon unblocking ortriggering the stopper driver, the liquid drug is expelled and thusinjected automatically without further user interaction. As it isintegrated into the cartridge holder, the distance that such apre-stressed spring has to travel in order to reach the stopper isindependent of the position of the cartridge holder, resulting in acontinuous and steady ejection of the liquid drug.

In an embodiment of the drug delivery device, a stopper driver fordriving the stopper in a distal direction is attached to the body. Asmultiple cartridges may be used with a single drug delivery devicecomprising a single stopper driver, such an embodiment may be morecost-effective and easier to manufacture and operate.

In an embodiment, the drug delivery device comprises a cartridge driverfor driving the cartridge from the retracted towards the advancedposition. As an advantage, the pulling force required to move thecartridge towards its advanced position may be reduced and an incompletepenetration of the septum by the proximal needle tip may be prevented.

In an embodiment, the cartridge driver comprises a pre-stressed springwhich is particularly easy and cost-effective to manufacture.

In an embodiment, the cartridge driver is adapted to be released ortriggered by pulling the cap, thereby relieving the user from theadditional burden of releasing the cartridge driver. Those skilled inthe art will acknowledge that other ways of releasing or triggering thecartridge driver are possible as well, such as pushing the sleeve or thebody or a part thereof.

In an exemplary embodiment, the drug delivery device comprises acartridge containing a drug.

Further scope of applicability of the present disclosure will becomeapparent from the detailed description given hereinafter. However, itshould be understood that the detailed description and specificexamples, while indicating exemplary embodiments of the disclosure, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the disclosure will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE FIGURES

The present disclosure will become more fully understood from thedetailed description given hereinbelow and the accompanying drawingswhich are given by way of illustration only, and thus, are not limitiveof the present disclosure, and wherein:

FIG. 1 is a longitudinal section of a drug delivery device with a capwith an angular recess and a cartridge holder in a retracted position,

FIG. 2 is a longitudinal section of a drug delivery device with a capwith an angular recess and a cartridge holder in an advanced position,

FIG. 3 is a longitudinal section of a drug delivery device with acartridge holder in an advanced position after removal of a cap with anangular recess,

FIGS. 4a-4d show a plurality of longitudinal sections of a drug deliverydevice with a cap with a partially folded collar in a sequence of stepsduring removal of the cap, and

FIGS. 5a-5d show a plurality of longitudinal sections of a drug deliverydevice with a cap with a partially folded collar in a sequence of stepsduring triggering of the drug delivery device.

Corresponding parts are marked with the same reference symbols in allfigures.

DETAILED DESCRIPTION

FIG. 1 shows a drug delivery device 1 with a body 2 in a longitudinalsection along a longitudinal axis A with a proximal end P and a distalend D. Inside the body 2, a cartridge holder 3 holds a cartridge 4comprising a liquid drug.

The cartridge 4 is fixated relative to the cartridge holder 3. Forexample, the cartridge 4 may be pressed into the cartridge holder 3 suchthat it is held by friction. On its distal end, the cartridge 4 issealed by a septum 4.1. On its proximal end, the cartridge 4 is sealedby a stopper 4.2 that is movable towards the distal end of the cartridge4.

The cartridge holder 3 with the cartridge 4 is movable along thelongitudinal axis A. On the proximal end of the cartridge holder 3, aclip 3.1 is arranged that protrudes in an outward radial direction, i.e.away from the central longitudinal axis A. An inclined flange of thisoutwardly radially protruding clip 3.1 engages an inwardly radiallyprotruding wedge 2.2 with a correspondingly inclined edge. Theinclination of the clip 3.1 and the corresponding inclination of theprotruding wedge 2.2 are formed as to resist a distal displacement ofthe cartridge holder 3 such that an inadvertent movement of thecartridge holder 3 is prevented. When a sufficient force pulls thecartridge holder 3 in a distal direction, this resistance is overcome asthe inclined flange of the clip 3.1 slides along the inclined edge ofthe protruding wedge 2.2, thereby slightly bending the body 2 outwardly.Once the clip 3.1 passed the wedge 2.2, the wedge 2.2 snaps beyond theproximal face of the clip 3.1 and blocks a proximal displacement of thecartridge holder 3.

An outwardly protruding stop 3.2 is formed on the cartridge holder 3such that it engages a corresponding inwardly protruding flange 2.3 onthe body 2 upon a predetermined distal displacement, thereby limitingthe distal displacement range of the cartridge holder 3 with thecartridge 4.

Inside the body 2, a needle holder 5 is formed as a socket with a flangeon its proximal end. The needle holder 5 is immovably attached to thebody 2, for example by a pod 6 with radially protruding ends 6.1, 6.2,wherein the proximal radially protruding end 6.1 engages a proximalflange of a radial protrusion 2.1 of the body 2 and wherein the distalprotruding end 6.2 engages the flange of the needle holder 5. Therebythe pod 6 prevents the needle holder 5 from withdrawing from the radialprotrusion 2.1 in a distal direction. In its centre, the needle holder 5holds a hypodermic needle 7. The needle 7 is immovable relative to theneedle holder 5. For example, the needle 7 may be pressed into a centralhole of the socket forming the needle holder 5 such that it is held byfriction.

The needle 7 has a proximal needle tip 7.1 adapted to penetrate theseptum 4.1 of the cartridge 4. In its retracted position shown in FIG.1, the cartridge holder 3 with the cartridge 4 is proximally displacedsuch that the proximal needle tip 7.1 does not reach the septum 4.1, butthe proximal needle tip 7.1 proximally protrudes the flange of theneedle holder 5 such that the proximal needle tip 7.1 safely penetratesthe septum 4.1 once the cartridge 4 is brought toward the needle holder5. The needle 7 also has a distal needle tip 7.2 adapted to penetratetissue on its distal end.

The distal part of the needle 7 is covered by a two-walled cap 8 thatcomprises an outer cap sheath 8.1, an inner cap sheath 8.2concentrically arranged within the outer cap sheath 8.1 and a distal capbottom 8.3. The inner cap sheath 8.2 holds a receptacle 8.4 thatreceives the distal part of the needle 7. The receptacle 8.4 may, forexample, be made of rubber with a central hole closely fitting thedistal part of the needle 7 such that the receptacle 8.4, and therebythe cap 8, are held by friction relative to the needle 7. By such areceptacle 8.4, the needle 7 is safely protected in a sterileenvironment. Those skilled in the art will appreciate that otherembodiments of needle receptacles can be arranged inside the cap 8 aswell.

The cartridge holder 3 comprises a bendable lever 3.3 protruding in adistal direction beyond the distal end of the cartridge 4 and furtherprotruding beyond the flange of the needle holder 5. A radiallyprotruding catch 3.4 is formed on the distal end of the lever 3.3 suchthat the tip of the catch 3.4 points towards the distal end D. Theflange of the needle holder 5 engages the lever 3.3 such that it isslightly bended in an outward radial direction, i.e. away from thecentral longitudinal axis A.

An angular recess 8.2.1 is formed into the outer surface of the innercap sheath 8.2 such that it receives the catch 3.4. Thereby, the catch3.4 and the angular recess 8.2.1 form a snap-in closing between thecartridge holder 3 and the cap 8. While the cap 8 can easily be pluggedonto the cartridge holder 3 during manufacturing, the snap-in closingformed by the catch 3.4 and the angular recess 8.2.1 locks the cap 8 andthe cartridge holder 3 when the cap 8 is pulled off the drug deliverydevice 1 in preparation of an injection.

In the following, preparing the drug delivery device 1 for an injectionis explained in more detail.

When the cap 8 is pulled off the drug delivery device 1, the pullingforce is transferred from the cap 8 via the catch 3.4 that is engaged inthe angular recess 8.2.1 onto the cartridge holder 3. Thereby, thecartridge holder 3 is displaced distally into its advanced position thatis shown in FIG. 2. In this advanced position, the cartridge 4 isbrought towards the proximal surface of the needle holder 5 causing theproximal needle tip 7.1 to penetrate the septum 4.1. The cartridgeholder 3 is locked in its advanced position by the stop 3.2 engaging theflange 2.3 and by the clip 3.1 engaging the wedge 2.2.

As the cartridge holder 3 moves from its retracted position in thedistal direction, the lever 3.3 is bended outwardly by the needle holder5. When the cartridge holder 3 reaches its advanced position, the lever3.3 is just sufficiently bended to cause the catch 3.4 to disengage fromthe angular recess 8.2.1, thereby releasing the cap 8 from the cartridgeholder 3.

It is possible that the drug delivery device 1 comprises a slidableneedle sleeve 9 that distally protrudes the body 2 to protect at least adistal part of the needle 7 to prevent needle stick injuries. In anembodiment, such a needle sleeve 9 is received in the space between theinner cap sheath 8.2 and the outer cap sheath 8.1. As it is shown inFIG. 3, in such an embodiment the cap 8 may be slid off the needlesleeve 9 once the catch 3.4 disengages from the angular recess 8.2.1.Pulling off the cap 8 is particularly easy, as the cartridge holder 3 islocked in its advanced position by the clip 3.1 and the stop 3.2, suchthat it cannot longer follow movements of the cap 8.

In an embodiment of the disclosure, the cartridge holder 3 further holdsa stopper driver 10 for driving the stopper 4.2 in a distal direction inorder to eject the liquid drug from the cartridge 4. The stopper driver10 may be formed as a pre-compressed spring 10 integrated into thecartridge holder 3. Those skilled in the art will appreciate that otherembodiments of a stopper driver are possible, such as a pre-compressedspring effecting between the stopper 4.2 and the body 2, for example apre-compressed spring arranged between the stopper 4.2 and the proximalend of the body 2.

FIGS. 4A-4D show longitudinal sections of an embodiment of a drugdelivery device 1 with a cap 18, depicting a sequence of steps forremoving the cap 18 from the drug delivery device 1 and therebypreparing the drug delivery device 1 for an injection. According to thisembodiment of the disclosure, the cartridge 4 has a cartridge wall 13.On the distal end of the cartridge the cartridge wall 13 has a shoulder13.1 with a proximal flange. The cap 18 is formed as a sheath with anopen proximal end, with a cap bottom 18.3 on its distal end and with acap sleeve 18.1. The cap sleeve 18.1 provides at least one cut-out18.1.2. On its proximal end, the cap sleeve 18.1 provides an at leastpartially folded collar 18.1.1.

The at least partially folded collar 18.1.1 of the cap 18 engages theproximal flange of the shoulder 13.1 when the cartridge (4) is in itsretracted position, as shown in FIG. 4A. A needle holder 15 is formed asa socket with a cylindrical side wall 15.1 and a bottom 15.2 on thedistal end of the side wall 15.1, holding the needle 7 in a central holeof the bottom 15.2. The bottom 15.2, and thereby the needle holder 15,is fixated relative to the body 12 by at least one holding member 12.1that is led through a cut-out 18.1.2 of the cap sleeve 18.1. The capsleeve 18.1 is concentrically arranged to the side wall 15.1 of theneedle holder 15. The proximal end of the cap sleeve 18.1 is led betweenthe body 12 and the needle holder 15.

The cap sleeve 18.1 may be formed by at least two circumference arms,wherein the folded collar 18.1.1 on the proximal ends of thesecircumference arms is formed as bended or folded splines that engage theproximal flange of the shoulder 13.1. The circumference arms are ledthrough openings 12.3 formed in the side wall of the body 12, such thatholding members 12.1 are attached to the body 12 and led throughcut-outs 18.1.2 in between the circumference arms forming the cap sleeve18.1.

When the cap 18 is pulled off the drug delivery device 1, it carries thecartridge 4 in a distal direction, thereby causing the proximal needletip 7.1 to penetrate the septum 4.1 of the cartridge 4, as shown in FIG.4B. Unfolding of the folded collar 18.1.1 is prevented by guiding thecap sleeve 18.1 inside a recess 12.2 in the inner surface of the body12. Those skilled in the art will appreciate that other embodiments ofguiding the cap sleeve 18.1 inside the body 12 are possible.

The folded collar 18.1.1 may unbend or unfold through the opening 12.3once the cartridge 4, carried by the cap 18, reached its advancedposition, as shown in FIG. 4C. In this advanced position, the distalsurface of the septum 4.1 engages the proximal surface of the bottom15.2 of the needle holder 15, wherein the side wall 15.1 proximallyprotrudes the proximal flange of the shoulder 13.1. This proximalprotrusion causes the folded collar 18.1.1 to unfold such that itdisengages from the shoulder 13.1 and is released from the cartridge 4,as can be seen from FIG. 4D. The cap 18 can thus be easily removed fromthe drug delivery device 1 that is prepared for the injection.

FIGS. 5A-5D show longitudinal sections of an further embodiment of adrug delivery device 1 with a cap 18, depicting a sequence of steps fortriggering the drug delivery device 1 and thereby advancing thecartridge 4 and the cap 18 forwards in the distal direction D forreleasing the cap 18 from the drug delivery device 1 and therebypreparing the drug delivery device 1 for an injection. According to thisembodiment of the disclosure, the drug delivery device 1 comprises atrigger button 19 and a drive element 20, e.g. a drive spring.

Further, the cartridge 4, the cap 18 and the needle holder 15 correspondto the similar components of the embodiment according to FIGS. 5A to 5D.

When the drug delivery device 1 is triggered by pressing the triggerbutton 19 in the distal direction D. The drive element 20 is releasedand thereby advancing the cartridge 4 forwards in the distal direction Drelatively to the needle holder 15, as can be seen from FIGS. 5B to 5D.Thereby, the proximal needle tip 7.1 penetrates the septum 4.1 of thecartridge 4, as shown in FIG. 5B.

Due to the coupling of the cartridge 4 and the cap 18, the cap 18 ispushed forwards in the distal direction D, too. Unfolding of the foldedcollar 18.1.1 is prevented by guiding the cap sleeve 18.1 inside arecess 12.2 in the inner surface of the body 12. Those skilled in theart will appreciate that other embodiments of guiding the cap sleeve18.1 inside the body 12 are possible.

The folded collar 18.1.1 may unbend or unfold through the opening 12.3once the cartridge 4, carried by the cap 18, reached its advancedposition, as shown in FIG. 5C. In this advanced position, the distalsurface of the septum 4.1 engages the proximal surface of the bottom15.2 of the needle holder 15, wherein the side wall 15.1 proximallyprotrudes the proximal flange of the shoulder 13.1. This proximalprotrusion causes the folded collar 18.1.1 to unfold such that itdisengages from the shoulder 13.1 and is released and, therefore,decoupled from the cartridge 4, as can be seen from FIG. 5D. The cap 18can thus be easily removed from the drug delivery device 1 that isprepared for the injection.

The terms “drug” or “medicament” are used herein to describe one or morepharmaceutically active compounds. As described below, a drug ormedicament can include at least one small or large molecule, orcombinations thereof, in various types of formulations, for thetreatment of one or more diseases. Exemplary pharmaceutically activecompounds may include small molecules; polypeptides, peptides andproteins (e.g., hormones, growth factors, antibodies, antibodyfragments, and enzymes); carbohydrates and polysaccharides; and nucleicacids, double or single stranded DNA (including naked and cDNA), RNA,antisense nucleic acids such as antisense DNA and RNA, small interferingRNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleic acids maybe incorporated into molecular delivery systems such as vectors,plasmids, or liposomes. Mixtures of one or more of these drugs are alsocontemplated.

The term “drug delivery device” shall encompass any type of device orsystem configured to dispense a drug into a human or animal body.Without limitation, a drug delivery device may be an injection device(e.g., syringe, pen injector, auto injector, large-volume device, pump,perfusion system, or other device configured for intraocular,subcutaneous, intramuscular, or intravascular delivery), skin patch(e.g., osmotic, chemical, micro-needle), inhaler (e.g., nasal orpulmonary), implantable (e.g., coated stent, capsule), or feedingsystems for the gastro-intestinal tract. The presently described drugsmay be particularly useful with injection devices that include a needle,e.g., a small gauge needle.

The drug or medicament may be contained in a primary package or “drugcontainer” adapted for use with a drug delivery device. The drugcontainer may be, e.g., a cartridge, syringe, reservoir, or other vesselconfigured to provide a suitable chamber for storage (e.g., short- orlong-term storage) of one or more pharmaceutically active compounds. Forexample, in some instances, the chamber may be designed to store a drugfor at least one day (e.g., 1 to at least 30 days). In some instances,the chamber may be designed to store a drug for about 1 month to about 2years. Storage may occur at room temperature (e.g., about 20° C.), orrefrigerated temperatures (e.g., from about −4° C. to about 4° C.). Insome instances, the drug container may be or may include a dual-chambercartridge configured to store two or more components of a drugformulation (e.g., a drug and a diluent, or two different types ofdrugs) separately, one in each chamber. In such instances, the twochambers of the dual-chamber cartridge may be configured to allow mixingbetween the two or more components of the drug or medicament prior toand/or during dispensing into the human or animal body. For example, thetwo chambers may be configured such that they are in fluid communicationwith each other (e.g., by way of a conduit between the two chambers) andallow mixing of the two components when desired by a user prior todispensing. Alternatively or in addition, the two chambers may beconfigured to allow mixing as the components are being dispensed intothe human or animal body.

The drug delivery devices and drugs described herein can be used for thetreatment and/or prophylaxis of many different types of disorders.Exemplary disorders include, e.g., diabetes mellitus or complicationsassociated with diabetes mellitus such as diabetic retinopathy,thromboembolism disorders such as deep vein or pulmonarythromboembolism. Further exemplary disorders are acute coronary syndrome(ACS), angina, myocardial infarction, cancer, macular degeneration,inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis.

Exemplary drugs for the treatment and/or prophylaxis of diabetesmellitus or complications associated with diabetes mellitus include aninsulin, e.g., human insulin, or a human insulin analogue or derivative,a glucagon-like peptide (GLP-1), GLP-1 analogues or GLP-1 receptoragonists, or an analogue or derivative thereof, a dipeptidyl peptidase-4(DPP4) inhibitor, or a pharmaceutically acceptable salt or solvatethereof, or any mixture thereof. As used herein, the term “derivative”refers to any substance which is sufficiently structurally similar tothe original substance so as to have substantially similar functionalityor activity (e.g., therapeutic effectiveness).

Exemplary insulin analogues are Gly(A21), Arg(B31), Arg(B32) humaninsulin (insulin glargine); Lys(B3), Glu(B29) human insulin; Lys(B28),Pro(B29) human insulin; Asp(B28) human insulin; human insulin, whereinproline in position B28 is replaced by Asp, Lys, Leu, Val or Ala andwherein in position B29 Lys may be replaced by Pro; Ala(B26) humaninsulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30)human insulin.

Exemplary insulin derivatives are, for example, B29-N-myristoyl-des(B30)human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoylhuman insulin; B29-N-palmitoyl human insulin; B28-N-myristoylLysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N—(N-palmitoyl-gamma-glutamyl)-des(B30) humaninsulin; B29-N—(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyheptadecanoyl) human insulin. Exemplary GLP-1, GLP-1analogues and GLP-1 receptor agonists are, for example:Lixisenatide/AVE0010/ZP10/Lyxumia,Exenatide/Exendin-4/Byetta/Bydureon/ITCA 650/AC-2993 (a 39 amino acidpeptide which is produced by the salivary glands of the Gila monster),Liraglutide/Victoza, Semaglutide, Taspoglutide, Syncria/Albiglutide,Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054,Langlenatide/HM-11260C, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926,NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697,DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030,CAM-2036, DA-15864, ARI-2651, ARI-2255, Exenatide-XTEN andGlucagon-Xten.

An exemplary oligonucleotide is, for example: mipomersen/Kynamro, acholesterol-reducing antisense therapeutic for the treatment of familialhypercholesterolemia.

Exemplary DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin,Saxagliptin, Berberine.

Exemplary hormones include hypophysis hormones or hypothalamus hormonesor regulatory active peptides and their antagonists, such asGonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin),Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin,Triptorelin, Leuprorelin, Buserelin, Nafarelin, and Goserelin.

Exemplary polysaccharides include a glucosaminoglycane, a hyaluronicacid, a heparin, a low molecular weight heparin or an ultra-lowmolecular weight heparin or a derivative thereof, or a sulphatedpolysaccharide, e.g. a poly-sulphated form of the above-mentionedpolysaccharides, and/or a pharmaceutically acceptable salt thereof. Anexample of a pharmaceutically acceptable salt of a poly-sulphated lowmolecular weight heparin is enoxaparin sodium. An example of ahyaluronic acid derivative is Hylan G-F 20/Synvisc, a sodiumhyaluronate.

The term “antibody”, as used herein, refers to an immunoglobulinmolecule or an antigen-binding portion thereof. Examples ofantigen-binding portions of immunoglobulin molecules include F(ab) andF(ab′)₂ fragments, which retain the ability to bind antigen. Theantibody can be polyclonal, monoclonal, recombinant, chimeric,de-immunized or humanized, fully human, non-human, (e.g., murine), orsingle chain antibody. In some embodiments, the antibody has effectorfunction and can fix complement. In some embodiments, the antibody hasreduced or no ability to bind an Fc receptor. For example, the antibodycan be an isotype or subtype, an antibody fragment or mutant, which doesnot support binding to an Fc receptor, e.g., it has a mutagenized ordeleted Fc receptor binding region.

The terms “fragment” or “antibody fragment” refer to a polypeptidederived from an antibody polypeptide molecule (e.g., an antibody heavyand/or light chain polypeptide) that does not comprise a full-lengthantibody polypeptide, but that still comprises at least a portion of afull-length antibody polypeptide that is capable of binding to anantigen. Antibody fragments can comprise a cleaved portion of a fulllength antibody polypeptide, although the term is not limited to suchcleaved fragments. Antibody fragments that are useful in the presentdisclosure include, for example, Fab fragments, F(ab′)2 fragments, scFv(single-chain Fv) fragments, linear antibodies, monospecific ormultispecific antibody fragments such as bispecific, trispecific, andmultispecific antibodies (e.g., diabodies, triabodies, tetrabodies),minibodies, chelating recombinant antibodies, tribodies or bibodies,intrabodies, nanobodies, small modular immunopharmaceuticals (SMIP),binding-domain immunoglobulin fusion proteins, camelized antibodies, andVHH containing antibodies. Additional examples of antigen-bindingantibody fragments are known in the art.

The terms “Complementarity-determining region” or “CDR” refer to shortpolypeptide sequences within the variable region of both heavy and lightchain polypeptides that are primarily responsible for mediating specificantigen recognition. The term “framework region” refers to amino acidsequences within the variable region of both heavy and light chainpolypeptides that are not CDR sequences, and are primarily responsiblefor maintaining correct positioning of the CDR sequences to permitantigen binding. Although the framework regions themselves typically donot directly participate in antigen binding, as is known in the art,certain residues within the framework regions of certain antibodies candirectly participate in antigen binding or can affect the ability of oneor more amino acids in CDRs to interact with antigen.

Exemplary antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab).

The compounds described herein may be used in pharmaceuticalformulations comprising (a) the compound(s) or pharmaceuticallyacceptable salts thereof, and (b) a pharmaceutically acceptable carrier.The compounds may also be used in pharmaceutical formulations thatinclude one or more other active pharmaceutical ingredients or inpharmaceutical formulations in which the present compound or apharmaceutically acceptable salt thereof is the only active ingredient.Accordingly, the pharmaceutical formulations of the present disclosureencompass any formulation made by admixing a compound described hereinand a pharmaceutically acceptable carrier.

Pharmaceutically acceptable salts of any drug described herein are alsocontemplated for use in drug delivery devices. Pharmaceuticallyacceptable salts are for example acid addition salts and basic salts.Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g.salts having a cation selected from an alkali or alkaline earth metal,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are known to those of skill in thearts.

Pharmaceutically acceptable solvates are for example hydrates oralkanolates such as methanolates or ethanolates.

Those of skill in the art will understand that modifications (additionsand/or removals) of various components of the substances, formulations,apparatuses, methods, systems and embodiments described herein may bemade without departing from the full scope and spirit of the presentdisclosure, which encompass such modifications and any and allequivalents thereof.

LIST OF REFERENCES

-   -   1 drug delivery device    -   2, 12 body    -   2.1 radial protrusion    -   2.2 wedge    -   2.3 flange    -   3 cartridge holder    -   3.1 clip    -   3.2 stop    -   3.3 lever    -   3.4 catch    -   4 cartridge    -   4.1 septum    -   4.2 stopper    -   5, 15 needle holder    -   6 pod    -   7 needle    -   7.1 proximal needle tip    -   7.2 distal needle tip    -   8, 18 cap    -   8.1 outer cap sheath    -   8.2 inner cap sheath    -   8.2.1 angular recess    -   8.3, 18.3 cap bottom    -   8.4 receptacle    -   9 needle sleeve    -   10 stopper driver    -   12.1 holding member    -   12.2 recess    -   12.3 opening    -   cartridge wall    -   13.1 shoulder    -   15.1 side wall    -   15.2 bottom    -   18.1 cap sleeve    -   18.1.1 folded collar    -   18.1.2 cut-out    -   19 trigger button    -   20 drive element    -   A longitudinal axis    -   D distal end    -   P proximal end

1-11. (canceled)
 12. A drug delivery device for dispensing a liquiddrug, the drug delivery device comprising: a body configured to house acartridge comprising the liquid drug, the cartridge sealed with a septumand with a movable stopper; a needle holder holding a needle with aproximal needle tip and a distal needle tip relative to the body; and acap adapted to cover at least the distal needle tip, wherein the cap isreleasably engaged with the cartridge and the cartridge is movablerelative to the body from a retracted position towards an advancedposition, and wherein, while moving the cartridge towards the advancedposition, the proximal needle tip pierces the septum and extends throughthe septum and the cap is being released from the cartridge (4), andwherein, when the cartridge reaches the advanced position, the cap isreleased from the cartridge.
 13. The drug delivery device according toclaim 12, wherein the cartridge is moved from the retracted positiontowards the advanced position when the cap is pulled off the drugdelivery device in the distal direction and such that the cap isreleased from the cartridge in the advanced position.
 14. The drugdelivery device according to claim 12, wherein the cartridge is held bya cartridge holder comprising a lever protruding in a distal directionbeyond the needle holder with a catch protruding on a distal lever endin an inwardly radial direction that is releasably engaged with anangular recess formed in an inner surface of the needle cap, wherein theneedle holder engages the lever such that the distal lever end is bendedin an outwardly radial direction when the cartridge holder is movedtowards the advanced position, thereby disengaging the catch from theangular recess.
 15. The drug delivery device according to claim 12,wherein an at least partially folded collar on a proximal end of a capsleeve of the cap releasably engages a shoulder of a cartridge wall ofthe cartridge and is guided in a guide recess formed between thecartridge wall and the body, and wherein a side wall of the needleholder proximally protrudes the shoulder when the cartridge wall reachesits advanced position, thereby causing the at least partially foldedcollar to unfold and disengage from the shoulder.
 16. The drug deliverydevice according to claim 15, wherein the cap sleeve is formed by atleast two circumference arms, each led through a side opening in thebody, and wherein the at least partially folded collar is formed bybended or folded splines on the proximal ends of the at least twocircumference arms.
 17. The drug delivery device according to claim 12,wherein a stopper driver for driving the stopper in a distal directionis integrated into the cartridge holder.
 18. The drug delivery deviceaccording to claim 12, wherein a stopper driver for driving the stopperin a distal direction is attached to the body.
 19. The drug deliverydevice according to claim 12, further comprising a cartridge driver fordriving the cartridge from the retracted towards the advanced position.20. The drug delivery device according to claim 19, wherein thecartridge driver comprises a pre-stressed spring.
 21. The drug deliverydevice according to claim 19, wherein the cartridge driver is adapted tobe released by pulling the cap.
 22. The drug delivery device accordingto claim 1, further comprising a cartridge containing a drug.